Pharmacophore Modeling and Docking Studies to Investigate Potential Leads for the Development of β -Secretase APP Cleavage Enzyme-1 (BACE-1) Inhibitors

Author(s): Richa Arya, Satya Prakash Gupta*, Sarvesh Paliwal, Swapnil Sharma, Kirtika Madan, Monika Chauhan.

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 7 , 2019

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Graphical Abstract:


Background: Alzheimer’s disease is a medical condition with detrimental brain health. It is majorly diagnosed in aging individuals plaque in β) characterized by accumulated Amyloidal beta (A 1 BACE) 1 secretase APP cleavage enzyme βneurological areas. The ) is the target of choice that can be exploited to find drugs against Alzheimer’s disease.

Methods: A series of BACE-1 inhibitors with reported binding constant were considered for the development of a feature based pharmacophore model.

Results: The good correlation coefficient (r=0.91) and RMSD of 0.93 was observed with 30 compounds in training set. The model was validated internally (r2test=0.76) as well as externally by Fischer validation. The pharmacophore based virtual screening retrieved compounds that were docked and biologically evaluated.

Conclusion: The three structurally diverse molecules were tested by in-vitro method. The pyridine derivative with highest fit value (6.9) exhibited IC50 value of 2.70 µM and thus was found to be the most promising lead molecule as BACE-1 inhibitor.

Keywords: β-secretase APP cleavage enzyme-1, β-secretase, docking, fluorescence, micro plate, pharmacophore, virtual screening.

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Article Details

Year: 2019
Page: [775 - 784]
Pages: 10
DOI: 10.2174/1570180815666181023110736
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